Project Summary/Abstract Chronic alcohol toxicity can result in alcoholic liver disease (ALD). This can result in liver cirrhosis? extensive fibrosis which disrupts normal liver architecture?often leading to liver failure. The vast majority of liver cancer (i.e., hepatocellular carcinoma) cases arise in the setting of cirrhotic liver. Currently, no targeted therapies are available to halt or reverse the fibrosis-cirrhosis-cancer progression. As fibrosis progresses, the liver becomes physically stiff. Recently, the importance of signaling pathways that cells use to interpret changes in mechanical cues has been recognized. Often disease processes arise due to misregulation of such signaling pathways. How the mechanical properties of the liver change as a result of alcohol toxicity and how this effects signaling is unknown. Understanding the molecular mechanisms governing mechanical signaling in the liver, therefore, could yield novel therapeutic targets for treating ALD, reversing fibrosis, and preventing liver cancer. I propose to answer two main questions: 1) How does alcohol influence the mechanical properties of the liver? And 2) How does increased liver stiffness influence ALD progression to fibrosis and cancer? My approach will take advantage of the unique properties of the zebrafish model system: external embryonic development, optical transparency, rapid transgenesis, high conservation of genes and organs with mammals, and the aquatic environment, which enables precise alcohol delivery. Professionally, it is my ultimate goal to establish an academic research career with a focus on mechanical signal transduction in human pluripotent stem cells and in zebrafish disease models. I am most interested problems with a clear impact on human disease. My graduate work focused on understanding mechanisms of human pluripotent stem cell differentiation. To complement this skillset, I chose to pursue postdoctoral research in Prof. Wolfram Goessling?s group due to his status as a leader in the zebrafish disease modeling and his technical expertise dissecting mechanisms of liver development and regeneration. This research career development plan will be mutually beneficial. I bring a strong background in mechanical signaling, and I will learn to apply this to zebrafish models of alcohol toxicity. In this way, I will learn new skills while maintaining high scientific productivity. Receiving this fellowship would facilitate my scientific training and expedite my progress toward becoming a fully independent biomedical researcher.